c.2519G→T This dominant missense mutation was identified in 32 members of a Norwegian family, and was characterized as an activating mutation. Affected patients had mild chronic diarrhea and an increased risk for several GI disorders. The role of this mutation in cancer susceptibility remains unclear (Fiskerstrand et al., 2012).

c.1160A>G This recessive missense mutation was identified in a Bedouin family, and was characterized as an inactivating mutation. Affected patients had perinatal meconium ileus secondary to impaired GUCY2C-mediated fluid secretion. The role of this mutation in cancer susceptibility remains unclear (Romi et al., 2012).

c.2270dupA This recessive nonsense mutation was identified in a Bedouin family, and resulted in a premature stop codon two amino acids following the insertion which resulted in a truncated GUCY2C protein lacking its catalytic domain. Affected patients had perinatal meconium ileus secondary to impaired GUCY2C-mediated fluid secretion. The role of this mutation in cancer susceptibility remains unclear (Romi et al., 2012).

The endogenous GUCY2C ligands, guanylin and uroguanylin, are lost early in the neoplastic process, resulting in inactivation of downstream tumor suppressive GUCY2C signaling. Targeted deletion of GUCY2C in mice results in a phenotype of intestinal cancer susceptibility in the context of predisposing genetic mutations (apcmin) or exposure to carcinogen (azoxymethane). GUCY2C has a wide range of homeostatic functions in preventing tumorigenesis, including regulation of crypt proliferation, DNA damage repair and oncogenic signaling such as PI3K/Akt (Li et al., 2007a; Li et al., 2007b; Lin et al., 2010).

Entity

Obesity

Note

GUCY2C is expressed in the hypothalamus, and targeted deletion in mice results in an obese phenotype which has been attributed to increased food consumption and dysregulated satiety. Importantly, the GUCY2C hormone ligand uroguanylin has been shown to mediate this effect. The uroguanylin peptide is released into the circulation postprandially and travels to the brain where it induces satiety in the hypothalamus, thus comprising a gut-brain neuroendocrine axis which regulates feeding (Valentino et al., 2011).

GUCY2C is a known mediator of intestinal fluid secretion. Work in mice and humans has demonstrated that the bacterial heat stable enterotoxin (ST) causes GI fluid secretion, motility and diarrhea via GUCY2C activation in the intestine. Recently, an oral GUCY2C ligand linaclotide (Linzess Ironwood Pharmaceuticals) was approved by the FDA for treatment of constipation-predominant irritable bowel syndrome (IBS). Further work has revealed a role for linaclotide in preventing GI pain associated with IBS. The mechanism for this effect is believed to be release of cGMP by enterocytes from their basolateral membrane following ligand activation. This cGMP then inhibits nociception in adjacent visceral neurons, relieving pain (Chey et al., 2012; Castro et al., 2013).

Entity

Inflammatory bowel disease (IBD) / colitis

Note

Work in mice has identified a possible role for GUCY2C in preventing colitis. Targeted deletion of GUCY2C results in more severe disease in a chemical model of colitis. Additionally, oral administration of GUCY2C ligand improved colitis in wild-type mice in the same model. These findings suggest a role for GUCY2C in regulating intestinal inflammation and associated disorders (Lin et al., 2012).

Entity

Attention deficit hyperactivity disorder (ADHD)

Note

Work in mice has demonstrated the presence of GUCY2C in midbrain neurons, and targeted deletion of GUCY2C resulted in a phenotype of hyperactivity, which was reversible by treating with either ADHD therapeutics or an activator of downstream GUCY2C signaling (PKG activator) (Gong et al., 2011).